The normal urethra is highly distensible. Therefore, upon relaxation of the urethral and periurethral musculature, a small increase in bladder wall tension results in high urine flow rates. However, in the face of either a functional or structural bladder outlet obstruction, an increased level of mechanical tension must develop in the bladder wall to overcome the increased resistance to urine outflow. To meet this need, the bladder wall hypertrophies. The hypertrophy is a result of both an increase in cell size (cellular hypertrophy) and cell number (cellular hyperplasia). If the bladder outlet obstruction is chronic, the hypertrophy becomes excessive. The derangement in urinary tract physiology that results from excessive bladder wall hypertrophy can result in such problems as chronic urinary tract infection secondary to poor emptying and renal failure secondary to vesicoureteral reflux. Because of the potential for these problems, we have sought to define the signal transduction pathways that mediate the bladder wall hypertrophic response to increased mechanical tension. We initiated our studies by focusing on the hyperplastic component of the response. We found that when there is a bladder outlet obstruction, expression of the F-box protein Skp2 is upregulated in the tissue of the bladder wall. Skp2 is important for the destruction of a protein, p27(KIP1), that inhibits cell cycle progression. Thus we thought that the increased expression of Skp2 would prove to be important in the bladder wall hyperplastic response to bladder outlet obstruction. We, therefore, examined the effect of bladder outlet obstruction in Skp2-knockout mice. Indeed, we found that the proliferative response that occurs when the normal bladder is obstructed is absent in the obstructed bladder of Skp2-knockout mice. This indicates that the upregulation of Skp2 is a critical component of the hyperplastic response to bladder outlet obstruction. We then examined the mechanism by which expression of Skp2 is upregulated when there is a bladder outlet obstruction. Importantly, whereas Skp2 is regulated by growth factors at the protein stability level, we found that the increase in mechanical tension that develops in the bladder wall secondary to a bladder outlet obstruction upregulates expression of Skp2 by increasing the rate of transcription of Skp2 RNA. Because of the importance of Skp2 expression in the hyperplastic response to bladder outlet obstruction, we will now attempt to delineate the signal transduction pathways that upregulate Skp2 expression when there is bladder outlet obstruction. These studies will be aimed at identifying targets for intervention to inhibit the hypertrophic response of the bladder wall that occurs in response to bladder outlet obstruction.